Explore the vast range of titles available.

Allogeneic stem cell transplantation (alloSCT) is an effective immunotherapy in patients with hematological malignancies. Endothelial dysfunction was linked to major complications after alloSCT. We asked the question if the “Endothelial Activation and Stress Index” (EASIX; [(creatinine × LDH) ÷ thrombocytes]) can predict mortality after alloSCT. We performed a retrospective cohort analysis in five alloSCT centers in the USA and Germany. EASIX was assessed prior to conditioning (EASIX-pre) and correlated with mortality in 755 patients of a training cohort in multivariable models. The predictive model established in the training cohort was validated in 1267 adult allo-recipients. Increasing EASIX-pre predicted lower overall survival (OS) after alloSCT, and successful model validation was achieved for the validation cohort. We found that EASIX-pre predicts OS irrespective of established scores. Moreover, EASIX-pre was also a significant prognostic factor for transplant-associated microangiopathy. Finally, EASIX-pre correlated with biomarkers of endothelial homeostasis such as CXCL8, interleukin-18, and insulin-like-growth-factor-1 serum levels. This study establishes EASIX-pre based on a standard laboratory biomarker panel as a predictor of individual risk of mortality after alloSCT independently from established clinical criteria.

Cancer patients frequently require central venous catheters for therapy and parenteral nutrition and are at high risk of central venous catheter–related infections (CRIs). Moreover, CRIs prolong hospitalization, cause an excess in resource utilization and treatment cost, often delay anti-cancer treatment, and are associated with a significant increase in mortality in cancer patients. We therefore summoned a panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and updated our previous guideline on CRIs in cancer patients. After conducting systematic literature searches on PubMed, Medline, and Cochrane databases, video- and meeting-based consensus discussions were held. In the presented guideline, we summarize recommendations on definition, diagnosis, management, and prevention of CRIs in cancer patients including the grading of strength of recommendations and the respective levels of evidence. This guideline supports clinicians and researchers alike in the evidence-based decision-making in the management of CRIs in cancer patients.

PurposeHemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome emerging from a deregulated immune response due to various triggers. In adults, systematic data are sparse, which is why recommendations on diagnosis and management have been adopted from pediatric guidelines. A nationwide clinical registry with associated consulting service as collaborative initiative of HLH-specialized pediatricians and hematologists was initiated to better characterize HLH in adults.MethodsPatients with proven or suspected HLH were registered by 44 institutions. Both HLH-2004 diagnostic criteria and the HScore (www.saintantoine.aphp.fr/score/) were used to confirm HLH diagnosis. Data referring to underlying disease, treatment, outcome, clinical presentation and laboratory findings were recorded.ResultsThe study included 137 patients and provides the first systematic data on adult HLH in Germany. Median age was 50 years with a wide range (17–87 years), 87 patients (63.5%) were male. Most common triggering diseases were infections in 61 patients (44.5%) and malignancies in 48 patients (35%). Virtually all patients had elevated ferritin concentrations, and 74% had peak concentrations greater than 10,000 µg/l. At time of analysis, 67 of 131 patients (51%) had died. Patients with malignancy-associated HLH had the shortest median survival (160 days), however no statistically significant difference between subgroups was observed (p = 0.077). Platelets under 20*109/l and low albumin concentrations (< 20 g/l) were associated with poor overall and 30-day survival.ConclusionClose multidisciplinary case consultation and cooperation is mandatory when treating adult HLH patients. Early contact with reference centers is recommended, especially in relapsing or refractory disease.

To ensure the safety of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT), evidence-based recommendations on infectious complications after HDC/ASCT are given. This guideline not only focuses on patients with haematological malignancies but also addresses the specifics of HDC/ASCT patients with solid tumours or autoimmune disorders. In addition to HBV and HCV, HEV screening is nowadays mandatory prior to ASCT. For patients with HBs antigen and/or anti-HBc antibody positivity, HBV nucleic acid testing is strongly recommended for 6 months after HDC/ASCT or for the duration of a respective maintenance therapy. Prevention of VZV reactivation by vaccination is strongly recommended. Cotrimoxazole for the prevention of Pneumocystis jirovecii is supported. Invasive fungal diseases are less frequent after HDC/ASCT, therefore, primary systemic antifungal prophylaxis is not recommended. Data do not support a benefit of protective room ventilation e.g. HEPA filtration. Thus, AGIHO only supports this technique with marginal strength. Fluoroquinolone prophylaxis is recommended to prevent bacterial infections, although a survival advantage has not been demonstrated.

Acute myeloid leukemia (AML) is a malignant disorder derived from neoplastic myeloid progenitor cells characterized by abnormal proliferation and differentiation. Although novel therapeutics have recently been introduced, AML remains a therapeutic challenge with insufficient cure rates. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies including acute lymphoblastic leukemia (ALL). However, the application of CAR-T cells appears to be challenging due to the enormous molecular heterogeneity of the disease and potential long-term suppression of hematopoiesis. Here we report on the generation of CD33-targeted CAR-modified natural killer (NK) cells by transduction of blood-derived primary NK cells using baboon envelope pseudotyped lentiviral vectors (BaEV-LVs). Transduced cells displayed stable CAR-expression, unimpeded proliferation, and increased cytotoxic activity against CD33-positive OCI-AML2 and primary AML cells in vitro. Furthermore, CD33-CAR-NK cells strongly reduced leukemic burden and prevented bone marrow engraftment of leukemic cells in OCI-AML2 xenograft mouse models without observable side effects.

Secondary haemophagocytic lymphohistiocytosis (sHLH) or Macrophage Activation Syndrome (MAS) is a life-threatening hyperinflammatory syndrome that can occur in patients with severe infections, malignancy or autoimmune diseases. It is also a rare complication of haematopoetic stem cell transplantation (HSCT), with a high mortality. It may be associated with graft vs. host disease in the allogeneic HSCT setting. It is also reported following CAR-T cell therapy, but differentiation from cytokine release syndrome (CRS) is challenging. Here, we summarise the literature and present results of a survey of current awareness and practice in EBMT-affiliated centres of sHLH/MAS following HSCT and CAR-T cell therapy. An online questionnaire was sent to the principal investigators of all EBMT member transplant centres treating adult patients (18 years and over) inviting them to provide information regarding: number of cases of sHLH/MAS seen in their centre over 3 years (2016-2018 inclusive); screening strategies and use of existing diagnostic/classification criteria and treatment protocols. 114/472 centres from 24 different countries responded (24%). We report estimated rates of sHLH/MAS of 1.09% (95% CI = 0.89-1.30) following allogeneic HSCT, 0.15% (95% CI = 0.09-5.89) following autologous HSCT and 3.48% (95% CI = 0.95-6.01) following CAR-T cell therapy. A majority of centres (70%) did not use a standard screening protocol. Serum ferritin was the most commonly used screening marker at 78% of centres, followed by soluble IL-2 receptor (24%), triglycerides (15%), and fibrinogen (11%). There was significant variation in definition of \"clinically significant\" serum ferritin levels ranging from 500 to 10,000 μg/mL. The most commonly used criteria to support diagnosis were HLH-2004 (43%) and the H score (15%). Eighty percent of responders reported using no standard management protocol, but reported using combinations of corticosteroids, chemotherapeutic agents, cytokine blockade, and monoclonal antibodies. There is a remarkable lack of consistency between EBMT centres in the approach to screening, diagnosis and management. Further research in this field is needed to raise awareness of and inform harmonised, evidence-based approaches to the recognition and treatment of sHLH/MAS following HSCT/CAR-T cell therapy.

Chimeric antigen receptor (CAR)-modified natural killer (NK) cells show antileukemic activity against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by the interaction between human leukocyte antigen (HLA)-E and the inhibitory receptor, NKG2A. Here, we describe a strategy that overcomes CAR-NK cell inhibition mediated by the HLA-E-NKG2A immune checkpoint. We generate CD33-specific, AML-targeted CAR-NK cells (CAR33) combined with CRISPR/Cas9-based gene disruption of the NKG2A-encoding KLRC1 gene. Using single-cell multi-omics analyses, we identified transcriptional features of activation and maturation in CAR33- KLRC1 ko -NK cells, which are preserved following exposure to AML cells. Moreover, CAR33- KLRC1 ko -NK cells demonstrate potent antileukemic killing activity against AML cell lines and primary blasts in vitro and in vivo. We thus conclude that NKG2A-deficient CAR-NK cells have the potential to bypass immune suppression in AML. NK cell-based therapy can kill acute myeloid leukemia (AML), but immune suppression may occur. Here the authors overcome the immunosuppression of AML-targeted CAR33-NK cells via non-viral CRISPR-editing of the immune checkpoint NKG2A, leading to an enhanced potency of the CAR-NK cell product with sustained anti-tumor efficacy.

There is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit anti-thymocyte globulin (rATG) is standard in Europe but post-transplantation Cyclophosphamide (PTCy) is an emerging alternative. We analyzed outcomes of rATG ( n  = 7725) vs. PTCy ( n  = 1039) prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen-matched unrelated donors (MUD) between January 2018 and June 2021 in the EBMT database. The provided P -values and hazard ratios (HR) are derived from multivariate analysis. Two years after alloSCT, NRM in the PTCy group was 12.1% vs. 16.4% in the rATG group; p  = 0.016; HR 0.72. Relapse was less frequent after PTCy vs. rATG (22.8% vs. 26.6%; p  = 0.046; HR 0.87). Overall survival after PTCy was higher (73.1% vs. 65.9%; p  = 0.001, HR 0.82). Progression free survival was better after PTCy vs. rATG (64.9% vs. 57.2%; p  < 0.001, HR 0.83). The incidence of chronic GVHD was lower after PTCy (28.4% vs. rATG 31.4%; p  = 0.012; HR 0.77), whereas the incidence and severity of acute GVHD were not significantly different. GVHD-free relapse-free survival was significantly higher in the PTCy arm compared to the rATG arm (2 y incidence: 51% vs. 45%; HR: 0.86 [95% CI 0.75–0.99], p  = 0.035). In the absence of evidence from randomized controlled trials, our findings support a preference for the use of PTCy in adult recipients of peripheral blood alloSCTs from MUD.

BackgroundCD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity.MethodsIn this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates.ResultsIn a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh (16% vs 46%, p<0.001), but not HTlow patients (0% vs 2%, p=n.s.). Collectively, HThigh patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThigh patients was observed (8.0% vs 3.7%, p=0.09).ConclusionsThese data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.

Hematologic and oncologic patients with chemo- or immunotherapy-related immunosuppression are at substantial risk for bacterial infections and Pneumocystis jirovecii pneumonia (PcP). As bacterial resistances are increasing worldwide and new research reshapes our understanding of the interactions between the human host and bacterial commensals, administration of antibacterial prophylaxis has become a matter of discussion. This guideline constitutes an update of the 2013 published guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). It gives an overview about current strategies for antibacterial prophylaxis in cancer patients while taking into account the impact of antibacterial prophylaxis on the human microbiome and resistance development. Current literature published from January 2012 to August 2020 was searched and evidence-based recommendations were developed by an expert panel. All recommendations were discussed and approved in a consensus conference of the AGIHO prior to publication. As a result, we present a comprehensive update and extension of our guideline for antibacterial and PcP prophylaxis in cancer patients.